Well over a decade ago, we demonstrated that the latent viral reservoir in the resting CD4+ T cell compartment persists in virtually all HIV-infected individuals receiving clinically effective ART. In addition, we demonstrated that HIV continually replicates at low levels in chronically infected individuals who are consistently aviremic during prolonged periods of receiving ART. Based on the above findings and similar observations from many other groups, the persistent viral reservoir has become a major impediment to the eradication of HIV in infected individuals receiving ART. In recent years, major research efforts have been dedicated to a better understanding of the pathogenesis of persistent HIV infection and to the development of therapeutic strategies aimed at eradicating virus in infected individuals receiving ART. During the past year, we have focused our research on: 1) examining the effects of recently discovered highly potent and broadly neutralizing HIV-specific antibodies on infectious virions derived from the latent HIV reservoir and on viral replication in autologous CD4+ T cells of infected individuals receiving ART and 2) exploring a therapeutic vaccine strategy aimed at achieving sustained virologic remission in infected individuals following the discontinuation of ART that had successfully suppressed viremia. Recent advances in antibody cloning technologies have led to the discovery of several highly potent and broadly neutralizing monoclonal antibodies against HIV from B cells of HIV-infected individuals. Several studies have demonstrated that certain broadly neutralizing HIV-specific antibodies can prevent acquisition of the virus, suppress viral replication, delay and/or prevent plasma viral rebound following treatment interruption in infected animals and block cell-to-cell transmission of laboratory-adapted HIV in vitro. However, it is unclear what in vivo effects these antibodies might have on HIV contained in persistently infected CD4+ T cells in infected individuals receiving ART. Given that this viral reservoir is considered to be a major obstacle to viral eradication as well as a potential source of plasma viral rebound following discontinuation of ART, it is of considerable interest to determine which of the many recently characterized HIV-specific broadly neutralizing antibodies can inhibit entry of HIV isolated from the latent viral reservoir into CD4+ T cells as well as inhibit replication of reservoir virus in autologous CD4+ T cells derived from infected individuals whose plasma viremia was well controlled while receiving ART. We first investigated which of the 9 broadly reactive HIV-specific antibodies (CD4-binding site on gp120: B12, VRC01, and VRC03; V1V2 site on gp120: PG9 and PG16; glycan-V3 site on gp120: PGT121 and 2G12; membrane proximal external region on gp41: 2F5 and 10E8) could prevent entry of HIV isolated from the latent viral reservoir into normal CD4+ T cells of infected individuals whose plasma viremia was well controlled by ART. Supernatants containing virus that was induced from the latent viral reservoir of the study subjects were pre-incubated with the 9 broadly reactive HIV-specific antibodies and human IgG (control) and the virus-antibody conjugates were then added to highly enriched and activated CD4+ T cells obtained from HIV-uninfected healthy donors. Following a 2-day incubation, the level of cell-associated HIV DNA was determined by droplet digital PCR. We demonstrated that the highest mean suppression of HIV entry was achieved by PGT121 (2.4 log), VRC01 (2.1 log), and VRC03 (1.8 log). The viral isolates from 72%, 52%, and 44% of HIV-infected individuals we studied were potently neutralized (>2 log suppression) by PGT121, VRC01, and VRC03, respectively. We also investigated whether certain HIV-specific monoclonal antibodies could suppress viral replication in an autologous setting. Highly enriched CD4+ T cells from 9 representative study subjects were stimulated with anti-CD3/CD28 antibodies in the presence of HIV-specific antibodies (individually or a paired combination) that were most effective in blocking viral entry for each study subject and the level of HIV replication was monitored by HIV p24 ELISA. Consistent with the viral entry data, PGT121, VRC01, VRC03 potently suppressed HIV replication. However, other HIV-specific monoclonal antibodies (such as PG9, PG16, and 10E8) that were less frequently effective in blocking entry of the virus from the overall cohort of infected individuals were equally effective at suppressing viral replication in those individuals whose virus was sensitive to these antibodies. Collectively, our data suggest that select HIV-specific monoclonal antibodies, such as PGT121, VRC01, and VRC03 can profoundly suppress HIV entry into CD4+ T cells and viral replication in stimulated autologous CD4+ T cells of infected individuals receiving ART. Considering that a complete eradication of HIV is not currently feasible in the majority of infected individuals, even under the best of circumstances involving early initiation of therapy, new approaches aimed at containing viral replication are being considered. The aim is not necessarily to achieve complete eradication of the virus, but rather to boost HIV-specific immune responses in order to keep plasma viremia in check upon discontinuation of ART. To this end, we recently launched a clinical trial entitled A phase I randomized, double-blind, placebo-controlled study of a multi-antigen DNA vaccine prime delivered by in vivo electroporation and a recombinant vesicular stomatitis virus (rVSV) booster vaccine in HIV-infected patients who began antiretroviral therapy during acute/early infection. This is an exploratory randomized, 2-arm (1:1, 15 patients per arm), double-blind, placebo-controlled trial evaluating the safety and efficacy of an HIV multi-antigen plasmid DNA vaccine prime, in combination with an interleukin-12 plasmid DNA adjuvant delivered in vivo by electroporation, and a rVSV vaccine boost in subjects receiving ART who initiated therapy during acute or early HIV infection. Study subjects are randomized to receive placebo or the multi-antigen HIV DNA vaccine at week 0, 4, 12, and 36, and placebo or the rVSV HIV gag booster vaccine at week 24 and 48. After the week 56 visit, all subjects undergo treatment interruption to determine if the vaccination strategy resulted in a reduction of viral replication, as evidenced by blunted or absent HIV plasma viremia. All subjects are followed throughout the 96-week period with frequent safety and efficacy assessments. Thus far, we have enrolled 26 of 30 patients in our trial and we anticipate completing enrollment by November 2014.